SUMMARY: Despite years of effort, an effective vaccine for HIV remains elusive. Perhaps the greatest obstacle to designing an effective vaccine is a lack of understanding of the immune responses necessary for protection from infection and/or clearance of virus from infected hosts. Furthermore, early cellular and molecular events, particularly in mucosal tissues of HIV infected patients are poorly understood. The latter are equally critical for vaccine development, since vaccines do not prevent infection, but instead limit viral replication to the site of transmission, and prevent amplification and subsequent spread of the virus to systemic sites or target organs that can result in disease. Several years ago we demonstrated the intestinal tract is the major target for early SIV infection, viral "ramp-up" amplification, and the major site of CD4+ T cell loss in SIV infected macaques, regardless of the route of infection, and it is now generally accepted that the intestinal tract is fundamental to the pathogenesis of early HIV infection. However, considerable controversy remains with regard to the earliest virologic and immunologic events in HIV infection, and correlates of immunity to infection or disease progression, which are both critical for developing novel vaccines or immunotherapeutics for prevention or control of infection. The proposed studies will utilize the rhesus macaque model of SIV infection to address the earliest events involved in infection of the intestine, as well as the role of mucosal immunity in control of infection. The specific aims are to;1) Determine how and when SIV reaches the gut following various routes of inoculation, and the earliest immunologic changes that accompany acute infection of mucosal tissues;2) Determine the relative contributions of bystander apoptosis and direct viral infection and killing of intestinal CD4+ T cells in acutely infected macaques in vivo, and;3) Identify the mechanisms of control of SIV in rhesus macaques infected with pathogenic SIV by comparing immunologic changes in mucosal and systemic tissue compartments between progressors, animals controlling infection (LTNP), and those on ART. Although tremendous advancements have been made in antiviral therapies, the rates of HIV infection continue to climb, and there are no vaccines, cures or reliable prevention strategies in the foreseeable future. Major hurdles in developing a vaccine remain in our lack of understanding of the earliest immunologic events associated with infection, as well as those associated with control of infection. The current proposal is to elucidate the earliest events in infection of mucosal tissues, and to compare mucosal and systemic immune responses in animals that are controlling infection in a relevant animal model. The ultimate objective is to discover key mechanisms involved in early infection and/or control of infection that may be exploited for developing new targets or approaches for vaccine design.